title: Acid-cleavable ketal containing poly(β-amino ester) for enhanced siRNA delivery.
abstract: The safe and effective intracellular delivery of nucleic acids remains the most challenging obstacle to the broad application of gene therapy in clinic. Endosomal escape of nucleic acids is also a major barrier for efficient gene delivery. Ketal linkage is known to readily cleave at the acidic pH of endosomal compartments. Here, we report ketal containing poly(β-amino ester) (KPAE) as an acid-cleavable non-viral siRNA delivery system. KPAE efficiently condensed siRNA into nanocomplexes with a diameter of ≈ 150 nm, which are stable under neutral conditions but rapidly dissociate to release siRNA at acidic pH. KPAE had a buffering capacity due to the presence of secondary amines in its backbone, confirmed by acid-base titration. Moreover, the studies of confocal fluorescence imaging using calcein and LysoTracker Red revealed that KPAE disrupted endosomes by colloid osmotic mechanism and "proton sponge" effects. Cell culture studies demonstrated that KPAE can deliver tumor necrosis factor-α (TNF-α) siRNA to lipopolysaccharide (LPS)-stimulated macrophages and significantly inhibit the expression of TNF-α. The results demonstrate that acid-cleavable KPAE has great potential as gene delivery systems based on its excellent biocompatibility, pH sensitivity and high gene delivery efficiency.
authors.affiliation: Polymer Fusion Research Center, Department of Polymer·Nano Science and Technology, Chonbuk National University, Jeonju, Chonbuk, 561-756, Republic of Korea.
authors.forename: Kyeonghye
authors.initials: K
authors.lastname: Guk
authors.forename: Hyungsuk
authors.initials: H
authors.lastname: Lim
authors.forename: Byungkuk
authors.initials: B
authors.lastname: Kim
authors.forename: Minsung
authors.initials: M
authors.lastname: Hong
authors.forename: Gilson
authors.initials: G
authors.lastname: Khang
authors.forename: Dongwon
authors.initials: D
authors.lastname: Lee
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018014:Gene Transfer Techniques; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D011108:Polymers / Q000008:administration & dosage* / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D011108:Polymers; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; C507253:poly(beta-amino ester)
keywords: Biodegradable polymer; Gene silencing; Poly(β-amino esters); pH-sensitive; siRNA